As a pioneer in the new wave of gene therapy treatments that have been steadily winding their way toward regulators with the promise of a once-and-done genetic fix for a wide range of ailments, bluebird bio $BLUE also got the first taste of the kind of backlash that can occur when a new technology fails to live up to the hope and hype that spurs billions of dollars of investments.

David Davidson

For bluebird, that moment of truth came a little more than two years ago, when the company reported that a handful of patients had inadequate responses to its gene therapy for sickle cell disease and beta-thalassemia. Company investigators went back to the drawing board, changed the manufacturing process on LentiGlobin with a new approach they had been working on that they felt would deliver a better gene therapy. And today they unwrapped a snapshot of the impact theyve had.

Bottom line: The first glimpse of human data looks promising.

The first three patients in bluebirds Phase III study for transfusion-dependent beta-thalassemia patients offered some of the human proof-of-concept data they were looking for, multiplying the number of cells they were delivering with corrective genes and producing a healthy flow of hemoglobin needed to correct the disease in the first patient that was evaluable at 6 months. Two other patients offered indications of a similar success though one of the patients also registered a positive but lower number of vector positive cells than the other two leaving bluebird execs hoping that they have the right potency in place for a durable cure.

That uneven response took a quick bite out of bluebirds shares Friday morning, sliding 6% in early trading.

This is an exciting validation of the changes in the manufacturing process, says bluebird CMO David Davidson. He explained: We added two small molecule enhancers transduction enhancers that we have been researching for many years, to find ways of increasing the efficiency of the viral vector to enter and integrate into stem cells.

Heres the slide on the first patients response from bluebirds presentation at the European Hematology Association meeting in Madrid, which the biotech shared with me in a preview.

That 13.3 grams per deciliter column on the right at 6 months includes a substantial amount of hemoglobin produced specifically by the therapy after transfusions were stopped.

It is, to be certain, a tiny number of patients and there are no guarantees in this business. But then bluebirds fortunes in gene therapy have always been decided by the responses of a handful of patients. Its pivotal Phase III data from which will be delivered to the FDA along with another late-stage trialinitially will recruit 15 adult and adolescent patients, then bring in 8 more children in an extension study. Theyll all be tracked for a considerable amount of time as investigators look for any variation in efficacy and safety.

Bluebird still has a long ways to go and isnt free of concerns on the safety front. Davidson also highlighted two patients who were hospitalized after experiencing acute gastroenteritis and acute chest syndrome in their earlier -205 study, though the company also believes that investigators are increasingly confident that they can avoid repeats in the future.

So bluebird takes another step down the late-stage pathway, with plans to seek an early, conditional approval in Europe based on the small early studies it completed.

European regulators have been a little more creative and more willing to advance these therapies forward than the FDA, Davidson adds. But they are advancing on both fronts today.

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Bluebird bio steps up with a promising snapshot of its gene therapy ... - Endpoints News

GenSight Biologics has raised(PDF) 22.5 million ($25.2 million) to prepare to bring gene therapy GS010 to market in the U.S. and Europe. The financing gives the Novartis-backed biotech enough cash to deliver data from two phase 3 trials next year and gear up for anticipated approvals on both sides of the Atlantic. Paris-based GenSight raised the cash from a mix of new and existing institutional investors, most of which are based in the U.S. Strong interest from these backers saw GenSight ease past its initial target of 20 million to pull in 22.5 million in the private placement. When added to the 48.8 million GenSight had in the bank at the end of March, management thinks the money moves its runway out to the first quarter of 2019. That runwaycovers a critical period for GenSight. Topline 48-week data from two phase 3 trials of GS010 in patients with Leberhereditary optic neuropathy (LHON) are due in the second and third quarters of next year. GenSight is looking to the trials for evidence GS010 improves the clarity of the vision of patients with LHON, a hereditary form of vision loss caused by mitochondrial defects. GS010 is injected into the eye to deliver the human wild-type ND4 gene via an adeno-associated virus to deliver. This gene encodes for a protein typically produced by mitochondria. One trial is assessing GS010 in patients who started losing their vision in the six months prior to enrolling in the study. The other is recruiting patients whose vision started deteriorating between seven and 12 months ago. Both trials are injecting GS010 into one eye of each participant and pretending to inject it into the other eye. Data from an earlier phase 1/2 trial suggest the gene therapy is most effective in patients whose vision started deteriorating less than two years ago. A recent 96-week update found the treated eyes of such patients had a mean gain of 29 ETDRS letters, as compared to an increase of 15 letters in untreated eyes. ETDRS is the test showing progressively smaller letters opticians use to gauge vision. The performance of GS010 to date has enabled GenSight to secure the support of some big-name backers. Following the latest financing, its biggest shareholders are Novartis, Versant, Abingworth and Fidelity. GenSight tried to turn this transatlantic support into a Nasdaq listing in 2015, but it was forced to downsize and ultimately scrap the plan in the face of an unreceptive market. GenSight was part of a clutch of European biotechs that arrived on Wall Street as the IPO window was closing. And like others from that group, including Basilea Pharmaceutica and Bavarian Nordic, it has so far held off on trying again in favor of raising cash from other sources.

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Novartis-backed GenSight gets cash for gene therapy launch - FierceBiotech

Sarepta Therapeutics is expanding its arsenal of drug development initiatives aimed at finding a treatment for Duchenne muscular dystrophy (DMD).

The biopharmaceutical company will collaborate with Genethon, a non-profit R&D organization to jointly create gene therapies for DMD.

Genethon specializes in a micro-dystrophin gene therapy approach that can target the majority of patients with DMD, according to the announcement. The organization has demonstrated proof-of-concept of their program through a robust gene expression in a large animal model of DMD.

Heres how this deal will work.

Genethon will handle the early development work. Sarepta will then have the option of co-developing and gaining exclusive licensing rights to products that emerge from Genethons micro-dystrophin program.

Our agreement with Genethon strengthens our ongoing commitment to patients and is aligned with our strategy of building the industrys most comprehensive franchise in DMD, said Sareptas Chief Executive Officer Edward Kaye, in a statement. This partnership brings together our collective experience in Duchenne drug development and Genethons particular expertise in gene therapy for rare diseases. We look forward to working with Genethon given their knowledge, large infrastructure and state-of-the-art manufacturing capabilities to advance next generation therapies for DMD.

This pact marks the second partnership pertaining to DMD that Sarepta formed this year.

The company announced in January that it signed a licensing agreement with Nationwide Childrens Hospital regarding their Galgt2 gene therapy program.

This initiative is aimed at exploring a surrogate gene therapy approach to Duchenne muscular dystrophy, which makes induced genes produce proteins that can basically do the same job as dystrophin, the protein people diagnosed with DMD are unable to make to generate normal muscle growth.

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Sarepta Signs Gene Therapy R&D Deal for DMD - Drug Discovery & Development

NobleGnthon has teamed up with ignominious Sarepta to develop a gene therapy for the Duchenne variety of the muscle wasting disease.

Dedicated to rare diseases since 1990 and more recently to gene therapy, Gnthon is one of veryfew not-for-profit companies in European biotech. Though it has not yet brought a drug to market, it is well established as a nonprofit, credit for which is due toits creator, the French Muscular Dystrophy Association, AFM Tlthon. The company has nowteamed up with the (in)famous American company, Sarepta, to work on a gene therapy for Duchenne Muscular Dystrophy (DMD).

DMD first affects the shoulder and upper arm muscles and the muscles of the hips and thighs. (Source: mda.org)

When I last spoke to Gnthons CEO,Frdric Revah, he told me that while the majority of the companys financial support comes from Tlthon, an increasing amount comes fromsuch partnerships.We get more and more support from industrial partnerships as we outlicense more of our drugs, explains Revah. However, Tlthon will always remain the main source of our funding; the funding from out-licensing is a complement.

But is Sarepta the best partner? While the American biotech can boast about its FDA-approved drug for DMD, Exondys 51, (which is just sold to Gilead for $125M,) this achievement isdubious:not only was the key clinical trial tiny, the FDAadmittedthat patients did not receive aclear benefit fromthe drug in the study. These circumstances prompted arenowned journalist to suefor thedocuments pertaining to the decision, an attack thatSareptas stock into a downward spiral in May.

Nevertheless, under the terms of the partnership agreement,Gnthon will trust Sarepta as a potential co-developer ofits DMD candidates, all of which are preclinical. The French biotechhas been developing amicro-dystrophin gene therapythat has proven itself applicable to the disease. As it countswith Europes largest cGMP vector manufactory, YposKesi, andone of the worlds largest research and clinical groups developing rare disease therapies, Gnthon is an attractive partner for any companies prospecting in the field.

Sareptas pricing practices may also offendthe sensibilities of a nonprofit, since theyraised the hackles of the drug pricing patrol with a plan to charge $300k per year for Exondys 51. According to STAT News, the companysCEO, Edward Kaye, saidthis figure isin the middle of the range for rare disease drugs,and given the sensitivity to pricing, we tried to be reasonable when looking at all the costs.

Though financial details of the agreement have not been disclosed, Gnthon may have enough influence to sway Sareptaaway from gouging.Our main goal is to ensure that patients have access to drugs and that they are affordable. Price should not be an obstacle,Revah told me.

Whatever we do here, we hope to apply the same tech to diseases that affect more people, like sickle cell anemia and cancer,he continued. With a crowded arena of companies like CRISPR Therapeutics, AMO Pharma, andDebiopharmall battling to bring the next DMD drug to market, having a back up plan via a platform seemssensible.

Images via Alila Medical Media, Anatomy Insider / shutterstock.com

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French Nonprofit Partners with Big American Name to Advance a Gene Therapy for Muscular Dystrophy - Labiotech.eu (blog)

Sarepta Therapeutics has penned its second DMD gene therapy pact this year as it announces a tie-up with Frances Genethon, a nonprofit R&D org.

The research collaborationwill see the Franco-American pair jointly develop treatments for Duchenne muscular dystrophy and comes after Sareptas first FDA approval for DMD with its controversial med Exondys 51 (eteplirsen).

RELATED: FDA expert lashes out at 'worrisome' Sarepta approval in JAMA

Sarepta is looking to tap into Genethons preclinical microdystrophin gene therapy approach, which can target the majority of patients with DMD. Its current med can only treat certain patients, namely those with the mutation of the dystrophin gene amenable to exon 51 skipping, which affects about 13% of the population with DMD.

It is hoping that with new tie-ups, it could produce a gene therapy that could treat many more, if not all, patients with the disease, although this is still some years off. DMD is a rare genetic disorder characterized by progressive muscle deterioration and weakness. The disease primarily affects young boysand occurs in about one out of every 3,600 male infants worldwide.

This builds on the pacts announced at the start of the year at the JPM conference, which saw it sign a deal with the Nationwide Childrens Hospital, which also focuses on the microdystrophin gene therapy program, as well as another form of gene therapy.

An initial phase 1/2a trial for the microdystrophin gene therapy is slated to begin at the end of the year and will be done at Nationwide Childrens. It also penned an exclusive license agreement with Nationwide for their Galgt2 gene therapy program, originally developed by researcher Paul Martin. This early-stage program aims to research a potential surrogate gene therapy approach to DMD, whereby the gene therapy looks to induce genes that make proteins that can perform a similar function as dystrophin. The goal will be to produce a muscle cell that can function normally even when dystrophin is absent, Sarepta said at the time.

Under the terms of its latest collaboration, Genethon will be responsible for the early development work. Sarepta has the option to co-develop Genethons microdystrophin program, which includes exclusive U.S. commercial rights. Financial terms, as is becoming more common with these pacts, have not been disclosed.

RELATED: With Exondys 51 approved, Sarepta chief Ed Kaye to bow out

Our agreement with Genethon strengthens our ongoing commitment to patients and is aligned with our strategy of building the industrys most comprehensive franchise in DMD, said Ed Kaye, Sareptas outgoing chief. This partnership brings together our collective experience in Duchenne drug development and Genethons particular expertise in gene therapy for rare diseases. We look forward to working with Genethon given their knowledge, large infrastructure and state-of the-art manufacturing capabilities to advance next generation therapies for DMD.

Frederic Revah, CEO of Genethon, added: Microdystrophin-based gene therapy is a very promising approach with potential application to a large majority of Duchenne patients. In order to accelerate the development of a treatment, we are very pleased to partner with Sarepta Therapeutics, which has demonstrated commitment and success for innovative therapies for Duchenne muscular dystrophy. This partnership brings together the highly complementary and synergistic expertises of Sarepta and Genethon, to the benefit of the patients.

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Sarepta signs another Duchenne gene therapy pact as it aims for wider treatment - FierceBiotech

San Francisco-based Vineti, a cell and gene therapy software and analytics company, has closed on Series A funding round that pulled together nearly $14 million.

Backing came from General Electric Ventures, Mayo Clinic and new investor Draper Fisher Jurvetson.

The company will use the funds to continue growing its team and to deliver cloud-based software to improve patient access. It also plans to speed its work on life-saving treatment delivery and to promote safety and FDA compliance for individualized cell therapies.

The Vineti platform integrates logistics, manufacturing and clinical data.

Physicians, medical researchers and pharmaceutical companies are working together to develop successful therapies, transitioning from a one-size-fits-all model to individualized treatments for each patient, Vineti CEO Amy DuRoss said in a statement. But, the process for administering these treatments is broken and outdated, restricting access to terminal patients and creating unnecessary risk.

DuRoss added that Vineti developed the platform to ensure treatments reach the patients who need them the most. She added that many patients who are excellent candidates dont have access to the most innovative therapies and discovery timelines are more challenging than necessary.

GE Ventures formed Vineti based on customer requests to bridge the technology gap between individualized cell therapies and production.

Modern technology solutions to address complex production and delivery processes are lacking. GE Ventures, Mayo Clinic and DFJ have invested in Vineti to rectify these problems.

Vineti is led by DuRoss, Chief Strategy Officer Heidi Hagen and CTO Razmik Abnous.

Twitter: @Bernie_HITN Email the writer: bernie.monegain@himssmedia.com

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Vineti to fast-track cell and gene therapy tech with $14 million first ... - Healthcare IT News

SAN FRANCISCO, Calif. Mayo Clinic Ventures has partnered with a California-based company to make cancer-fighting gene therapies available to the public.

Vineti, a pioneering cell and gene therapy software and analytics company, announced Tuesday that it had completed its initial round of funding raising $13.75 million aimed at delivering "the first cloud-based software solution to improve patient access, accelerate life-saving treatment delivery, and promote safety and regulatory compliance for individualized cell therapies."

The funding was provided by Mayo Clinic Ventures, GE Ventures, DFJ and LifeForce Capital. It's just the 15th company that Mayo Clinic Ventures has backed since it was formed, according to Andy Danielson, vice chairman of Mayo Clinic Ventures.

"One thing with Vineti that we liked is that we have a commitment to cell and gene therapies at Mayo," Danielson told TechCrunch.com. "Vineti will make the gene and cell therapy production process more efficient and as a result, less costly. It's all part of the equation of making these therapies more affordable and opening them up to a greater number of people."

The targeted cancer therapy under development by Vineti is part of a thriving field that conducted more than 800 clinical trials in 2016 while investing nearly $6 billion. It's all aimed at positively impacting the oncology field, the largest market in medicine that's expected to grow to $165 billion by 2021.

The first two cell therapies are expected to hit the market later this year.

Vineti touts its plans as one that "integrates logistics, manufacturing and clinical data to improve product performance overall and enable faster, broader access for patients."

"Physicians, medical researchers and pharmaceutical companies are working together to develop successful therapies, transitioning from a one-size-fits-all model to individualized treatments for each patient," said Amy DuRoss, CEO at Vineti. "Now, the process for creating and delivering these treatments can be as innovative as the therapies themselves. We are developing the Vineti platform to help these treatments reach the patients who need them the most, and are confident the partnership between our advances technologies and leading medical research will deliver better outcomes across the globe."

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Mayo Clinic Ventures funds new cancer-fighting cell, gene therapy ... - Post-Bulletin

British drugmaker GlaxoSmithKline made headlines last year when it won approval for its gene therapy Strimvelis in Europe. But, due to a small patient population and high price tag, the drug has only been used once. So far, despite higher levels of safety and efficacy than previous iterations, the new wave of gene therapies still face commercial hurdles.

Spark Therapeutics looks set to be the next company to take on this challenge in the U.S. The biotech is currently awaiting approval of its treatment for a rare genetic form of blindness a potential one-time cure. Yet pricing will be the most closely watched aspect of this therapy, likely serving as an early barometer of what might be sustainable for a pipeline of treatments still in development.

While gene therapy offers the promise of cures and new ways of revolutionizing treatment of genetic diseases, society remains a long way from fully realizing those advances.

After decades of setbacks, a slew of next-gen gene therapies are ready to hit the U.S. market, prompting questions about manufacturing and pricing. Read More >>

A pricing conundrum and ethical decisions are clouding an already hazy path to market for many gene therapy drugs and providers. Read More >>

With an approval of Spark Therapeutics' gene therapy for a rare eye disease rapidly approaching, new questions about pricing are being raised. Read More >>

In a field shaped by small patient populations and eye-popping cost considerations, understanding gene therapy's promise and challenges comes down, in part, to the numbers. Read More >>

While many are optimistic about gene editing's ability to cure disease, it seems not enough realize the more dangerous aspects of treatment. Read More >>

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Gene therapy: What you need to know - BioPharma Dive

Behind the incredible process of developing targeted gene therapies to fight diseases like cancer lies an incredibly mundane problem that prevents these treatments from getting to patients paperwork and procedures.

While $5.7 billion was invested in companies developing cellular and genetic therapies, and with 800 clinical trials initiated worldwide and the first two CAR-T cell therapies expected to launch into market later this year, businesses still saythe ability to get these treatments to patients is limited by paperwork, supply chain management, and last mile delivery.

So GE (through its GE Ventures arm), the Mayo Clinic (through Mayo Clinic Ventures) and the venture investment firm DFJ have invested $13.75 million to back Vineti a software platform the companies are billing as a solution to gene therapys supply chain problem.

Its only the sixth company to have actually been built by GEs internal business team and spun out by the conglomerates venture arm.

According to company co-founder and former GE Ventures managing director Amy DuRoss, the process for developing and managing gene therapies is critical to the success of the treatment.

Amy DuRoss, chief executive at Vineti

To that end, Vinetis software tracks logistics, manufacturing and clinical data to improve treatments and drive down the cost of these therapies (which are mainly only accessible to those people with the very best health plans).

The startups technology was actually born out of necessity (always the mother of invention) and came from conversations that GE was having with a large, undisclosed customer.

A pharma company that is a regular client of GE Healthcare said we are solving late stage cancer and we want to take this commercial but we have not got the technology that can ensure that we can scale out these technologies in the commercial phase, DuRoss told me.

GEs healthcare business then took the problem to the companys venture investment and new business arm and began the development process of building a business.

In addition to DuRoss, who has been a luminary in the life sciences field since she helped with the push to get stem cell research approved in California; Vineti has a murderers row of leading healthcare talent.

Chief strategy officer Heidi Hagen, was the former SVP of Operations for cell immunotherapy pioneer Dendreon; chief technology officer Razmik Abnous was the chief technology officer at the healthcare data management juggernaut Documentum; and Malek Faham, the companys chief science officer, literally worked on some of the foundational science for gene therapies.

While the companys technology could have applications for a number of different treatments, and be used for several kinds of therapies, the focus, for now, is on cancer.

Cancer is a bullseye, says DuRoss. It is arguably the biggest cause of human suffering [and] there are treatments already in phase three, that if brought to market effectively could mark a turning point in medicines battle against the deadly disease, she said.

We see an opportunity as data accrues to the system over time for a use case in predicting therapy based on outcome data but were not making these claims today, said DuRoss.

Mayo Ventures had been working with GE for two years from the initial concept to the close of this new round of financing for Vineti. Its one of only 15 companies that the Clinic has backed since the formation of Mayo Clinic Ventures, and according to Andy Danielsen, the vice chair of Mayo Clinic Ventures.

One thing with Vineti that we liked is that we have a commitment to cell and gene therapies at Mayo, said Danielsen, so the interests were aligned. Vineti will make the gene and cell therapy production process more efficient and as a result, less costly. Its all part of the equation of making these therapies more affordable and opening them up to a greater number of people.

Therapy supply chain

External ordering pages

Product tracking

Therapy scheduling

Identity verification

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GE and the Mayo Clinic back software to bring cancer-fighting gene ... - TechCrunch

"We are thrilled to have Chris join Brammer at this key time of our growth. Chris brings a unique blend of commercial and clinical manufacturing experience with deep gene therapy knowledge and an outstanding leadership ethos that will strengthen Brammer's presence as the best in class gene therapy CDMO," said Mark Bamforth, Brammer's President and CEO.

Chris started his career at American Cyanamid (now Pfizer) in Pearl River, NY, where he held positions in quality control, viral vaccine development, and bulk manufacturing.He later joined BioReliance in Rockville, MD, with responsibility for US contract manufacturing operations, focused primarily on viral vector manufacturing and cell banking in support of gene therapy pre-clinical and clinical studies.

Regarding joining Brammer, Chris shared, "I am passionate about the gene therapy industry and excited to be joining the leading gene therapy CDMO.Gene therapy will improve lives and transform healthcare in the coming years.Brammer is uniquely positioned with exceptional scientific know-how and top class manufacturing and quality operations. I am delighted to join a team that has honed its expertise through the delivery of over 150 clinical batches and is now preparing to supply phase III and commercial gene therapy products for clients."

"Chris's experience manufacturing viral vectors and his understanding of their quality attributes together with his commercial manufacturing track record is unique. He is a great addition to our team," noted Richard Snyder, Ph.D., Brammer's CSO.

Chris holds a Bachelor's degree in Biological Sciences from Rutgers University Cook College and a Master's degree in Biochemistry from New York Medical College. Chris is active in the community including serving as Vice Chairman, Board of Directors for Massachusetts Biotechnology Education Foundation and on the Board of Directors for the West End House Boys and Girls Club of Boston.

About BrammerBrammer Bio is a leading CDMO providing clinical and commercial supply of vectors for in vivo gene therapy and ex vivo modified-cell based therapy, along with process and analytical development, and regulatory support, enabling large pharma and biotech clients to accelerate the delivery of novel medicines to improve patients' health. Brammer is owned by Ampersand Capital Partners, the only institutional investor in the company, and its founders. For more information, please visit http://www.brammerbio.com

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Brammer Bio Appoints Leading Commercial Manufacturing And Gene Therapy Expert As Chief Manufacturing Officer - PR Newswire (press release)

LONDON--(BUSINESS WIRE)--Cell Medica today announced the acquisition of Catapult Therapy TCR Limited, a subsidiary of Cell and Gene Therapy Catapult (CGT Catapult), and the initiation of a collaboration to establish cell therapy manufacturing for Cell Medica at CGT Catapults GMP manufacturing facility in Stevenage, UK. Financial terms were not disclosed.

Catapult Therapy TCR Ltd is a special purpose company set up by CGT Catapult, UCL Business and Imperial Innovations, and managed by CGT Catapult, for the development of the WT1 T cell receptor (TCR) cell therapy discovered through research at University College London (UCL) and Imperial College London. The WT1-TCR cell therapy enhances the immune system to fight cancer by genetically engineering the patients T cells to target WT1, a tumour-associated antigen which is expressed in both solid tumours and blood cancers.

CGT Catapult has been developing the WT1-TCR cell therapy for the treatment of acute myeloid leukaemia and myelodysplastic syndrome. Early development work, including initiation of a Phase I trial, was conducted at UCL and Imperial College London with funding from the UK charity Bloodwise. CGT Catapult advanced the product to a larger Phase I/II clinical trial and developed an improved manufacturing process. Having completed the treatment of eight patients with promising results, CGT Catapult will now transfer the WT1-TCR cell therapy rights to Cell Medica for continued development towards regulatory approval.

The WT1-TCR cell therapy will be integrated with the Dominant TCR platform technology which Cell Medica licensed from UCL Business in 2016. Applying the Dominant TCR technology to the WT1-TCR cell therapy is expected to result in a more efficacious product with the potential to treat patients with solid tumours such as mesothelioma and ovarian cancer, which have proven very difficult to treat with conventional therapies. Cell Medica is planning to initiate a Phase I/II clinical trial with a Dominant WT1-TCR version in late 2018.

Cell Medica and CGT Catapult have also initiated a collaboration to establish cell therapy manufacturing operations for Cell Medica at the GMP production facility recently built by CGT Catapult in Stevenage. The collaboration will include transferring the current WT1-TCR cell therapy manufacturing process to Stevenage over the next twelve months while Cell Medica and CGT Catapult work to develop a commercial scale production process using advanced manufacturing techniques. Cell Medica will also evaluate the feasibility of manufacturing additional cell therapy products at the site.

The acquisition of the WT1-TCR cell therapy leverages the investment we made in 2016 for exclusive rights to the Dominant TCR technology, said Gregg Sando, CEO of Cell Medica. Our objective is to show how we can enhance any existing TCR cell therapy with the Dominant TCR technology to create a more effective treatment for patients with solid tumours who otherwise have a very poor prognosis. We are also looking forward to an important collaboration with CGT Catapult to initiate manufacturing at the Stevenage GMP facility where we will work together on scale-up strategies for commercial production.

About Cell Medica

Cell Medica is committed to transforming patients lives through developing the significant therapeutic potential of cellular immunotherapy for the treatment of cancer. In collaboration with our strategic partners, Cell Medica is developing a range of products using three proprietary technology platforms including activated T cells, chimeric antigen receptors (CARs) and engineered T cell receptors (TCRs). Our lead product is CMD-003 is being tested in an international Phase II trial for the treatment of cancers associated with the oncogenic Epstein Barr virus. We are working with the Baylor College of Medicine and the University of North Carolina to develop next generation CAR-modified NKT cells including an off-the-shelf product. In the field of engineered TCRs, we are collaborating with University College London to develop the Dominant TCR technology platform. Cell Medica is headquartered in London with subsidiaries in Zurich and Houston.

About the Cell and Gene Therapy Catapult

The Cell and Gene Therapy Catapult was established as an independent centre of excellence to advance the growth of the UK cell and gene therapy industry, by bridging the gap between scientific research and full-scale commercialisation. With more than 120 employees focusing on cell and gene therapy technologies, it works with partners in academia and industry to ensure these life-changing therapies can be developed for use in health services throughout the world. It offers leading-edge capability, technology and innovation to enable companies to take products into clinical trials and provide clinical, process development, manufacturing, regulatory, health economics and market access expertise. Its aim is to make the UK the most compelling and logical choice for UK and international partners to develop and commercialise these advanced therapies. The Cell and Gene Therapy Catapult works with Innovate UK. For more information please visit ct.catapult.org.uk or visit http://www.gov.uk/innovate-uk.

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Cell Medica Acquires WT1 Cancer Immunotherapy from Cell and ... - Business Wire (press release)

The term butterfly children sounds pleasant but refers to a harsh reality: children with epidermolysis bullosa, or EB, an inherited, genetic blistering skin disorder, are born withskin as fragile as a butterflys wings.

EB affects all races, ethnicities and both genders, and has no cure. According to the Dystrophic Epidermolysis Bullosa Research Association of America, every year about 200 children are born with EB in the United States.

There are several types of EB. The most common type of severe EB is recessive dystrophic epidermolysis bullosa, or RDEBa progressive, devastatingly painful and debilitating disease that affects up to ~2,500 patients in the U.S. and often leads to death. RDEB causes severe blistering and areas of missing skin in response to any kind of friction, including normal rubbing and scratching.

Cause of RDEB

RDEB is an autosomal recessive, inherited skin disease caused by null mutations within the type VII collagen gene (COL7A1). The mutations cause an absence or reduction of functional collagen VII (COL7), which make up anchoring fibrils that maintain binding of the epidermis to the dermis. The disease is characterized by a mechanical fragility and repeated blister formation in the sub-lamina densa at the level of the structurally defective anchoring fibrils.

Development of a New Gene Therapy

Fibrocell, a gene therapy company, is applying its distinctive autologous fibroblast technology to develop FCX-007, its candidate for the treatment of RDEBand potentially the first investigational therapy to target the underlying cause of the disease.

FCX-007 is being developed in collaboration with Intrexon Corporation, a leader in synthetic biology.

FCX-007 is an autologous dermal fibroblast genetically modified to express functional COL7 that is missing or deficient in RDEB patients. Transduced with a lentiviral vector containing COL7A1, FCX-007 is injected directly into the papillary dermis of blisters and wounds where the COL7 protein could enable formation of anchoring fibrils to hold the layers of skin together. The goal of the therapy is to provide high levels of functional COL7 directly to the affected areas while avoiding systemic distribution. This localized therapeutic approach is compatible with the unique biology of each individual patient.

The U.S. Food and Drug Administration (FDA) has granted Orphan Drug Designation to FCX-007 for the treatment of Dystrophic Epidermolysis Bullosa, which includes RDEB; likewise, the FDA granted both Rare Pediatric Disease and Fast Track Designations to FCX-007 for the treatment of RDEB.

A poster presented at the American Society of Human Genetics Annual Meeting in October 2015 addressed the preclinical development of FCX-007 for the treatment of RDEB. As noted in the poster, in vitro product development data indicates that cGMP scale FCX-007 cells express full-length COL7 exhibiting the proper trimeric structure, size and binding functionality.

Production of the lentiviral vector (LV-COL7) was successful, resulting in an infectious titer of ~9 x 106 IU/mL. The integrated transgene copy number per cell was dependent on the virus dose. FCX-007 was produced by expanding fibroblasts from skin biopsies, transducing with the vector, followed by subsequent expansion, harvest and cryopreservation. The COL7 expression from the FCX-007 cells was confirmed by ELISA and Western Blot as well as qRT-PCR and immunofluorescence staining.

The structure of expressed COL7 was confirmed to be predominantly trimeric by immunoprecipitation/SDS-PAGE/Western blot analysis. The COL7 produced from the FCX-007 cells was demonstrated to be functional by binding to Laminin332 in an in vitro binding assay as well as by correction of the hypermotility phenotype of RDEB cells in an in vitro migration assay.

The presentation also reported in vivo results from a preclinical animal model evaluating FCX-007 in RDEB and normal human skin xenografts implanted onto the dorsum of immunodeficient SCID mice. The grafts consisted of human fibroblasts and keratinocytes in a bilayer. The goals of the study were to confirm persistence, distribution and localization of COL7, and to evaluate any potential for product toxicity or vector biodistribution.

The composite RDEB skin grafts were injected intradermally with 1 x 106 FCX-007 cells and analyzed by immunofluorescent staining with human COL7 specific antibodies. Localization of COL7 was observed in composite grafts 10 days post-injection. Positive control grafts generated from normal keratinocytes and fibroblasts showed intense COL7 staining and negative control grafts did not show COL7 staining at baseline measurements.

In a follow-up toxicology/biodistribution study, FCX-007 was well tolerated up to six months post-administration.

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Developing a Gene Therapy with Transformative Potential for Patients with Recessive Dystrophic Epidermolysis Bullosa - Drug Discovery &...

Reviewed by Edwin M. Stone, MD, PhD

Though gene therapy technology already exists to treat most inherited retinal disease, the current challenge is to drive down the costs of implementing the technologythus availing more patients with the benefits of treatments and possibly prevent inevitable visual deterioration.

Edwin M. Stone, MD, PhD, recounted the case of a 14-year-old boy with an inherited eye disease who was born deaf and received bilateral cochlear implants during the first years of his life. The boys visual acuity levels were 20/25 and 20/32 in the right and left eyes, respectively. Despite good visual acuity, more recently, he had been having difficulty seeing in dim light.

A Goldmann perimetry evaluation showed normal responses to large, bright stimuli. However, there was some restriction at the 12e and 14e isopters, explained Dr. Stone, director, Stephen A. Wynn Institute for Vision Research, and professor, Department of Ophthalmology and Vision Sciences, University of Iowa, Iowa City.

A fundus examination showed that both discs were normal and the vessels were slightly constricted. Some pigmentation was present in the midperipheral retina.

Based on these findings, deafness at birth, and retinitis pigmentosa at the beginning of the second decade of life, the patient was given a diagnosis of type I Usher syndrome. Molecular testing showed the presence of the two most common mutations in the USH1C gene, i.e., Val72Val (a splice variant) and Thr78insC.

Read more from the original source:

Tapping gene therapy potential for inherited retinal diseases - ModernMedicine

A delivery for ALS? AveXis is currently using the gene therapy vector NAV AAV9, developed by REGENXBIO in Maryland, to deliver its experimental gene therapy for SMA into the spinal cord. The approach, which aims to increase levels of SMN, is beginning to show signs of benefit including motor function according to interim phase 1 results presented by Nationwide Childrens Hospitals Jerry Mendell and colleagues at the 2017 meeting of the American Academy of Neurology in Boston. [Image: National Human Genome Research Institute.]

AveXis is one step closer to developing a potential gene therapy for SOD1 ALS. The gene therapy company, based in Cleveland, Ohio, announced this month it has obtained the rights to develop treatments for ALS using REGENXBIOs gene therapy delivery vehicle. The emerging vector, derived from adeno-associated virus 9 (AAV9), is being increasingly utilized to deliver potential therapies into the CNS for neurological diseases.

The strategy is one of a growing number of potential gene therapies for SOD1 ALS that aims to reduce levels of misfolded SOD1 in the CNS and in the muscles by silencing the expression of the SOD1 gene (see May 2017 conference news). The approach is being developed by a research team led by Nationwide Childrens Hospitals Brian Kaspar in Ohio, who is also AveXis chief scientific officer and scientific founder (see December 2015 conference news; Thomsen et al., 2014; Foust et al., 2013).

The delivery vehicle, known as NAV AAV9, forms the basis of AveXis experimental gene therapy for the motor neuron disease spinal muscular atrophy (SMA). The strategy, known as AVXS-101, is currently being evaluated at the phase 1 stage at Nationwide Childrens Hospital as a treatment for Type 1 SMA, the most severe form of the disease. The approach builds on previous studies in 2009 led by Institute of Myologys Martine Barkats in France and Brian Kaspar in the United States, which found that AAV9 could cross the blood-brain barrier and therefore, could be used to potentially treat motor neuron diseases (seeDecember 2008news;Duque et al., 2009;Foust et al., 2009).

Meanwhile, Martine Barkats, in collaboration with Maria Grazia Biferi, in France is using a different approach in hopes to treat SOD1 ALS (see May 2017 conference news). The strategy, which uses a related gene therapy delivery vehicle known as AAV10, also aims to reduce motor neuron toxicity by silencing the expression of the SOD1 gene. The strategy is currently being optimized and is at the preclinical stage. The researchers are now developing a similar strategy in hopes to treat C9orf72 ALS, the most common form of the disease.

***

To learn more about gene therapy and its potential for ALS, check out our recent news feature: A New Potential Gene Therapy Delivers A Key Milestone.

References

Thomsen GM, Gowing G, Latter J, Chen M, Vit JP, Staggenborg K, Avalos P, Alkaslasi M, Ferraiuolo L, Likhite S, Kaspar BK, Svendsen CN. Delayed disease onset and extended survival in the SOD1G93A rat model of amyotrophic lateral sclerosis after suppression of mutant SOD1 in the motor cortex. Neurosci. 2014 Nov 19;34(47):15587-600. [PubMed].

Foust KD, Salazar DL, Likhite S, Ferraiuolo L, Ditsworth D, Ilieva H, Meyer K, Schmelzer L, Braun L, Cleveland DW, Kaspar BK. Therapeutic AAV9-mediated suppression of mutant SOD1 slows disease progression and extends survival in models of inherited ALS. Mol Ther. 2013 Dec;21(12):2148-59. [PubMed].

Duque S, Joussemet B, Riviere C, Marais T, Dubreil L, Douar AM, Fyfe J, Moullier P, Colle MA, Barkats M. Intravenous administration of self-complementary AAV9 enables transgene delivery to adult motor neurons. Mol Ther. 2009 Jul;17(7):1187-96. [PubMed].

Foust KD, Nurre E, Montgomery CL, Hernandez A, Chan CM, Kaspar BK. Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes. Nat Biotechnol. 2009 Jan;27(1):59-65 [PubMed].

Further Reading

van Zundert B, Brown RH Jr. Silencing strategies for therapy of SOD1-mediated ALS. Neurosci Lett. 2017 Jan 1;636:32-39. [PubMed].

Tora MS, Keifer OP Jr, Lamanna JJ, Boulis NM. The challenges of developing a gene therapy for amyotrophic lateral sclerosis. Expert Rev Neurother. 2017 Apr;17(4):323-325. [PubMed].

AAN2017 aav9 c9orf72 disease-als gene therapy SOD1 vector

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Gene Therapy Biotech AveXis Targets SOD1 ALS - ALS Research Forum

For many patients, participating in gene therapy clinical trials isnt an option because their immune system recognizes and fights the helpful virus used for treatment. Now, University of Florida Health and University of North Carolina researchers have found a solution that may allow viruses used for gene therapy to evade the bodys normal immune response.

The discovery, published in the Proceedings of the National Academy of Sciences, is a crucial step in averting the immune response that prevents many people from taking part in clinical trials for various disorders, according to co-author Mavis Agbandje-McKenna, Ph.D., a professor in the University of Florida College of Medicine department of biochemistry and molecular biology and director of the Center for Structural Biology.

During gene therapy, engineered viruses are used to deliver new genes to a patients cells. While the recombinant adeno-associated virus, or AAV, is effective at delivering its genetic cargo, prior natural exposure to AAV results in antibodies in some people. As many as 70 percent of patients have pre-existing immunity that makes them ineligible for gene therapy clinical trials, Agbandje-McKenna said.

The findings provide a road map for designing virus strains that can evade neutralizing antibodies, said Aravind Asokan, PhD, an associate professor in the department of genetics at the University of North Carolina School of Medicine, who led the study.

University of Florida first identified the structural footprints where pre-existing antibodies interact with the virus, using an cryo-electron microscope. The UNC researchers then evolved new viral protein shells. Using serum from mice, rhesus monkeys, and humans, the researchers showed that the redesigned virus can slip past the immune system.

This is the blueprint for producing AAV strains that could help more patients become eligible for human gene therapy. Now we know how to do it, Agbandje-McKenna said.

While the findings prove that one variation of AAV can be evolved, further study in preclinical models is needed before the approach can be tested in humans. Next, the immune profile of one particularly promising virus variant will need to be evaluated in a larger number of human serum samples, and dose-finding studies are needed in certain animal models. Researchers may also need to study whether the same virus-manipulating technique can be used in a broader range of gene therapy viruses, Agbandje-McKenna said.

Although human gene therapy remains an emerging field and has yet to reach patients on a wide scale, researchers elsewhere have used AAV therapy to successfully treat hemophilia, a blood-clotting disorder, in a small trial. It has also been or is now being studied as a way to treat hereditary blindness, certain immune deficiencies, neurological and metabolic disorders, and certain cancers.

The latest findings are the result of more than 10 years of studying the interactions between viruses and antibodies and a long-standing collaboration with Asokan, who heads the synthetic virology group at the UNC Gene Therapy Center.

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Newly Designed Viral Vectors Could Lead to Improved Gene Therapies - Bioscience Technology

Gene therapies have been in clinical development for decades, a winding, stop-and-start path toward transforming science's understanding of the genome into commercial therapies. Strimvelis, a gene therapy made by the British pharma GlaxoSmithKline and approved in Europe last year, will be a high-profile test of the viability of selling cures to a tiny handful of patients.

A broader pipeline, though, backs up an emerging field that could soon begin delivering new therapies to patients in need. Biotechs like Spark Therapuetics and BioMarin have promising gene treatments in late-stage development, and big pharmas like Pfizer and GlaxoSmithKline are active in exploring market opportunities in the space.

Only two gene therapies for inherited diseases have been approved for commercial sale in the Western world, both in Europe.

UniQures Glybera was the first to market, authorized under a five-year conditional approval for treatment of an ultra-rare genetic disorder known as familial lipoprotein lipase deficiency. Yet, Glyberas $1 million price tag and low demand (only one patient was ever treated) meant the therapy never gained any traction. In April, UniQure decided against seeking renewal of its marketing authorization when it lapses this October.

Gene therapy got some new momentum after GlaxoSmithKline won approval from the European Commission in May 2016 for Strimvelis, an ex-vivo stem cell gene therapy for a disease called ADA-SCID, perhaps better known as the "bubble boy" disease.

GlaxoSmithKline

Strimvelis is considered the first outright cure for a genetic disease, although its not known if the 100% survival rate seen in clinical trials will persist over a lifetime. Median duration of follow-up at the time of approval was seven years.

The cost of Strimvelis.

Cures dont come cheap. GlaxoSmithKline priced Strimvelis at 594,000 ($669,000), which after Glyberas $1 million pricetag and Strimvelis' better efficacy profile, was actually lower than what some had expected.

With more gene therapies in development, pricing will be a critical problem to solve for drugmakers seeking to commercialize genetic fixes particularly against the backdrop of the ongoing debate over how to price and value drugs.

One-time treatments that promise to deliver cures will clearly be priced higher than existing therapeutics. But its not just the high cost that will be an issue. If a drugmaker markets a cure with all costs paid upfront, the insurer and patient will hold the risk if the gene therapy stops working after, say, 10 years.

In addition, when patients in the U.S. are free to move from insurer to insurer as they change jobs and move through life, why would one insurer pay $500,000 or $1 million upfront if that patient is free to change insurance?

Estimated number of patients affected by ADA-SCID in Europe each year.

ADA-SCIDs ultra-rare nature underscores the challenge of successfully marketing a gene therapy. While some rare diseases have a sizable enough patient population to support a product commercially, others like ADA-SCID occur so infrequently that even a cure like Strimvelis might not actually make much money for GlaxoSmithKline.

The shelf life of freshly transduced cells for treatment with Strimvelis.

With Strimvelis, stem cells are taken from a patients bone marrow, inserted with a correct copy of the ADA gene using a viral vector, and then infused back into the patient, who has received low dose chemotherapy to improve engraftment.

Due to the limited window of time for infusion, GlaxoSmithKline only offers Strimvelis at the San Raffaele Hospital in Milan, Italy, which is near a cell processing laboratory.

While production and dosing procedures for other gene therapies will be different, manufacturing and logistical challenges are weightier than with small molecules or even biologics.

Since the drug is a patients own modified cells, chain of custody and supply chain visibility are crucial. Managing treatment at its own center simplifies things, but also makes it more difficult for patients to access treatment.

In 2003, the Food and Drug Administration temporarily halted 27 gene therapy trials amid safety concerns.

While Strimvelis and a full pipeline of gene therapies in testing have buoyed optimism in the field, progress from gene therapies hasnt been a straight line.

The FDA decided to suspend the 27 studies, which represented around 15% of the total number of gene therapy trials then underway, after two children developed leukemia-like symptoms in a French study. The new concern followed the 1999 death of Jesse Gelsinger, who had reacted to a gene therapy he received for a metabolic disorder.

The number of worldwide clinical trials for gene therapy or gene-modified cell therapy, according to numbers cited by the Alliance for Regenerative Medicine (ARM) in an annual report.

Thirty-one are in Phase 3, reflecting the progress in clinical development. Spark Therapeutics, for example, recently completed an application submission for U.S. approval of voretigene neparvovec in patients with a type of inherited retinal disease. The therapy, developed in collaboration with Pfizer, is one of the most high-profile candidates in the U.S.

Other well-known names such as BioMarin and Bluebird Bio are also making progress on treatments for beta thalassemia and hemophilia A, respectively.

Total amount of global financing for gene and & gene modified cell therapy companies raised last year, according to ARM.

That figure includes sums raised by a variety of means such as upfront payments, IPOs, venture rounds and partnerships.

Much of the work developing gene therapies has been driven forward by biotech companies, but big pharmas are starting to notice too.

Last summer, Pfizer put down $150 million upfront to acquire Bamboo Therapeutics, with another $495 million in milestones to shareholders lined up. More recently, the pharma giant paid $70 million upfront with $475 million in milestones to work with Sangamo Therapeutics on its hemophilia A gene therapies.

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Gene therapy by the numbers - BioPharma Dive

Hit-and-run story makes police look really inept

You have got to be kidding me.

A serious crime is committed (hit and run) with substantial bodily injury and property damage. When reporting the accident, the injured party says the person responsible has fled the scene, and the dispatcher asks: Do you still want an officer to respond?

Really? That must have instilled great confidence that a professional investigation was under way.

The initial responding officer fails to collect and protect physical evidence. Fortunately, the family of the injured party does. That's the extent of it for 16 days, until a complaint is made to the mayor.

The next officer on the case is able to identify the owner of the other vehicle. That person does not cooperate. So that's the end of it. Really? You can't bring him in for questioning?

Put Tom Lyons on the case and he will get it done really.

John Corning, Venice

Frontier not profiting from 'bogus billing'

The implication in Tom Lyons June 12 column that Frontier Communications somehow profits from customer billing issues is untrue and unjustified.

As with any company, our customers are our lifeblood. Our intent, in every interaction, is to provide reliable communications services.

When we let a customer down, we are accountable and do our best to fix the problem as quickly as possible. We offer sincere apologies and remedy the issue, making the customer whole. Often this includes credits for the customer quite the opposite of benefiting from bogus billing.

Frontier has made solid improvements over the past year and we will continue to sharpen our service. We live in and support the communities we serve, and our only goal is to be better.

Melanie Williams, Senior Vice President-Operations, Florida, Frontier Communications

Gene therapy article strikes home for reader

Regarding the June 6 article on the gene therapy of Stefanie Joho:

This article is very close to my heart. My husband Steve was diagnosed with cancer in 2005 and has been a patient since 2009 of Dr. Richard Brown, an oncologist at Florida Cancer Specialists in Sarasota.

In November 2015, Steve's chemotherapy was no longer effective. We were fearful and feeling desperate. Ironically, Jimmy Carter's remarkable life-saving treatment with a new immunology drug Keytruda (Merck pharma) was in the forefront of the news.

At Steve's next appointment, we told Dr. Brown that we had learned through a friends son, a breast cancer researcher, that Merck wanted to test Keytruda on other cancers. Dr. Brown, always Steve's advocate, told us that the practice had already discussed Steve. He would contact Merck.

It was determined Steve was a candidate and would qualify for the trial. He enrolled immediately. The rest is history!

The drug "suppressed a mutation" in his DNA. It attacked the cancers growth. Steve is no longer in the trial. He continues to receive an infusion treatment every three weeks and so far, so good!

Happily, life goes on and we owe a debt of gratitude to all the selfless researchers who have opened a new frontier in cancer treatment. Dr. Brown revealed that more options will be coming as they make new discoveries.

Good luck and long life to Stefanie!

Donna Jablo, Lakewood Ranch

Atlanta Braves play with taxpayers' money

In their quest for a cushy deal on their spring training facility, the Atlanta Braves were rebuffedby Palm Beach County and twice by Collier County, but have been welcomed with open arms by the easy marks in Sarasota County.

The pending deal will be another screw job unleashed on taxpayers by politicians offering huge subsidies to billionaire owners and multimillionaire players.

According to reports in the Herald-Tribune and elsewhere, the amount of public taxpayer money potentially allocated is:

$20 million from the Florida Sports Foundation, which, thanks to the Legislature and governor, is taxpayer-supported and hands out grants to special-interest groups like the Braves.

$22 million from the county tourism tax, which is paid by guests who stay in hotels and motels and largely used to fund special-interest groups rather than go into general revenues to benefit overburdened taxpayers. According to the Herald-Tribune, the requested amount is below the amount that would require public-referendum approval.

$300,000 a year paid by North Port for maintenance.

Also, West Villages is donating land worth $7 million to $9 million and paying for improvements.

Now, as reported in the Herald-Tribune, the county administrator and financial management officer suggest that a millage increase may be in store.

They play and you pay.

William Allen, Longboat Key

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Saturday's letters: Hit-and-run, Frontier, gene therapy, Braves - Sarasota Herald-Tribune

Once upon a time, gene therapy was thought to be the miracle of science that was going to change everything. After safety issues and patient deaths, that didnt work out quite like the industry had hoped.

Yet, 20 years later, the next generation of gene therapies is coming of age. These drugs so far have proven to be safer and more effective, but are raising new issues around cost. Many of the gene therapies being developed have the potential to be one-time treatments begging the question, how do you pay for something that could cure you after one dose?

This is the conundrum facing Spark Therapeutics, the West Philadelphia biotech poised to bring the first gene therapy to the U.S. market. Spark recently submitted an application to the Food and Drug Administration for voretigene neparvovec, a one-time gene therapy for the treatment of patients with vision loss due to confirmed biallelic RPE65 mutation-associated retinal disease a rare genetic disorder that causes blindness. The company completed its rolling Biologics Licensing Application on May 18 and is awaiting confirmation from the FDA that it has been accepted. An approval could come by mid-2018 or earlier.

Spark CEO Jeff Marrazzo has said publicly that the company has been having conversations with payers and is prepared to take on the challenge of drug pricing.

"We founded Spark in 2013 and began thinking about it 2011. I spent five years working in government, working on matters of healthcare reform before there was the Affordable Care Act, so I have some perspective on at least from a government and policy perspective what people are thinking about. And with respect to Spark, none of our conversations about getting patients access began after someone increased a price, or someone tweeted about it or wrote an article about it. We were having these conversations long before any of that," said Marrazzo at the BIO CEO conference in New York on Feb. 14.

While the company has been thinking about pricing for some time, Spark has been mum about how it actually intends to the price voretigene neparvovec.

"With respect to gene therapy, I think it really has the potential to reframe what we are talking about, and [move the conversation toward] talking more about health than healthcare. What we talk about and pay for, specifically on a transactional basis, is healthcare, and more and more thats how we are reimbursed. I think what we need to move to is to paying more toward health," added Marrazzo.

"Were engaging in productive conversations with payers, both private and public, and are encouraged by the discussions so far. Were finding that theres broad agreement that the current payment system is not designed to reward the long-term value created by gene therapy," added Marrazzo in an email to BioPharma Dive.

Marrazzos hope that a new path with alternative pricing models can be created may be an overly optimistic one. U.S. payers have been slow to adopt new pricing models for other drug classes. Even outcomes-based pricing models are still few and far between.

"Gene therapies are single, one-time interventions with the potential to deliver sustained, life-altering benefits to patients, families and healthcare systems. At this early stage, we are exploring potential payment, distribution and reimbursement models where we might address budgetary concerns or be paid for performance to further align with the potential long-term benefits of our investigational therapies. Clearly, different gene therapies may call for different pricing models in different markets," said Marrazzo to BioPharma Dive.

Jeff Marrazzo at BIO CEO

Lisa LaMotta, Editor BioPharma Dive

If Europe is any indication, alternative pricing models for gene therapies are not on the horizon. The first gene therapy hit the EU market in 2012, brought to patients with an ultra-rare disease by small biotech UniQure. Glybera (alipogene tiparvovec) was priced at about $1 million for a treatment a single treatment like what Spark offers. Reportedly, it was only ever used on one patient and while that patient has been reportedly doing well, Glybera was a commercial failure. UniQure opted not to renew the drugs marketing authorization in the EU in April, finally abandoning all effort into the therapy.

The failed Glybera experiment makes it clear that one-time administration gene therapies cannot follow the typical rare disease-pricing model. For the last several years, rare disease drug makers have been able to price their therapies at a higher rate upwards of $300,000 annually in many cases due to the extremely small patient populations and the lack of other available treatments. While this isnt ideal, most patients dont pay the full cost due to rebates and discounts, and the small patient populations mean there is less burden on the healthcare system overall. This pricing model is increasingly coming into question as drug makers develop more and more rare disease treatments, and the costs continue to climb.

Alternative pricing models have been proposed for one-time, or extremely long-acting, therapies such as those currently being developed for hemophilia. While these models are purely theory at the moment and likely far from reality, there has been talk of putting patients on a payment plan, having them make payments on a one-time treatment like a mortgage. The model would rely on the premise that as long as a patient continues to be healthy, they pay towards the treatment (at least for a set number of years or once a certain price cap is reached).

Yet, Spark has backed away from making concrete comments on the topic. The company has eluded and analysts believe it will stick with a single high price tag as per the typical rare disease model.

"Part of whats important to understand, we can come up with all sorts of various alternatives, but we have [to propose] an alternative that the other party can accommodate and succeed with. We dont want to have an approval and then waste time trying to come up with the perfect payment model," said Marrazzo at BIO CEO.

Until the agency grants an approval, the public is unlikely to get more details on the price for voretigene neparvovec. In the meantime, Spark is prepping its launch. The company has started a patient and physician education plan, as well as a genetic testing initiative.

Through a program dubbed ID YOUR IRD, the company is providing free, simple and fast access to genotyping. In addition, the medical field team is working to locate previously identified inherited retinal disease (IRD) patients at leading eye institutions.

"We have invested in disease education and built strong relationships with the patient advocacy community, demonstrating Sparks commitment to improving patient care through new models of diagnosis, delivery and access," Marrazzo added."Weve proactively engaged with regulators throughout the development of investigational voretigene neparvovec. In parallel, weve had many conversations with payers and experts both in the United States and in Europe to characterize the burden of disease and consider carefully the value that investigational voretigene neparvovec may provide."

Even if commercialization preparation goes well, payers may push back. Other rare disease drugs that have reached the market lately have not gotten the warm reception that they expected.

For instance, Sarepta Therapeutics recently approved Duchenne muscular dystrophy drug Exondys 51 (eteplirsen) is not being received well by payers, despite a patient population of children that has advocated for the drug for years. Several major insurers have refused to cover the drug or only cover it on a limited basis that makes a $300,000 a year treatment very hard to afford.

For Spark and other gene therapy drugmakers that follow, there will be an uphill battle as they enter an environment rife with public criticism about drug pricing.

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Alternative pricing models a fantasy for gene therapies? - BioPharma Dive

GenSight has announced Phase I/II data revealing that its gene therapy technology can restore sight in patients suffering from a rare mitochondrial disease.

GenSight Biologics develops gene therapies targeting degenerative diseases that cause blindness. The French biotech has now announced very promising results from its lead candidate, GS010, after 2 years of following patients treated with the gene therapy in an ongoing Phase I/II trial. Thetreatment targets Leber hereditaryoptic neuropathy (LHON), a rare genetic disease for which there is no curative treatment.

Patients sight was evaluated using the ETDRS test, the one consisting on recognizing increasingly smaller letters that most of us have done at some point in our life. Those patients treated with GS010 showed a statistically significant improvement in the number of letters they were able to recognize over time, especially in those that were treated within two years after their diagnosis. Detailed results after 96 weeks of follow-upare now pending publication in a peer-reviewed journal.

TE: treated eye; UTE: untreated eye

According to GenSight, 95% of LHON cases are caused by mutations in the genes that encodes the NADH dehydrogenase complex, which is involved in ATP metabolism within mitochondria. Since it affects amitochondrial gene, the disease is maternally inherited. GenSight is particularly focusing on patients with a mutation in the ND4 gene, which accounts for 70% of LHON cases in Europe and North America and up to 85% in Asia.

GenSight is already running two Phase III studies in Europe and the US evaluating GS010 in patients with the ND4 mutation that have been affected by LHON for a year or less.We are now less than a year away from Phase III efficacy data, and more than ever committed to find a cure for patients and their families affected by this devastating condition, said Bernard Gilly, CEO and co-founder of Gensight, in a statement. Philip recently interviewed him regarding his impressive track in biotech as both a serial entrepreneur and a partner at the VC firm Sofinnova.

So far, GenSight seems to be the only biotech developing a gene therapy for this disease. Ocular disorders are often rare,which leads most companies in the field to focus on age-related macular degeneration instead, which has a significantly higher prevalence. The French biotechs pipeline also includes GS011, a gene therapy to treat the ND1 mutation in LHON, still in the early research stage. The company is also working in GS030, an optogenetic gene therapyto introduce a protein that can respond to light with the aim of restoring sight in patients with retinitis pigmentosa, currently undergoing preclinical investigation.

Images via HQuality / Shutterstock; GenSight

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French Biotech Reports Sight Restoration thanks to Gene Therapy - Labiotech.eu (blog)

Gene therapy has finally made it over the hump.

After decades of research and some devastating setbacks, major technical hurdles have been overcome, opening up the long-anticipated promise of this field. A new approval has buoyed interest, pipelines are bubbling with new candidates and big investments are being made.

Two gene therapies have hit the European market and the first is expected to hit the U.S. market as early as next year. Beyond that, there is a growing pipeline rapidly coming forward.

All this is fueling high hopes of actual cures for previously incurable diseases and big profits. So whats the rub?

The first ever approved gene therapy was Shenzhen SiBiono GenTechs Gendicine, a recombinant Ad-p53 gene therapy for head and neck cancer, which launched in China in 2004. But it was Glybera's (alipogene tiparvovec) approval in fall 2012 that sparked investor interest in gene therapy. For a while that drug reigned as the most expensive treatment in history, costing more than $1 million per patient.

Glybera turned out to be a disappointment due to the high price tag. The drug restores lipoprotein lipase enzyme activity in patients with LPL deficiency (an ultra rare disease), but the drug comes with the severe side effect of pancreatitis. After use by only one patient and five years on the European market, maker uniQure chose not to seek renewal of its European approval this fall and is not pursuing U.S. approval.

Despite the failure of Glybera, GlaxoSmithKlines Strimvelis has further fueled investor interest with its approval in Europe in May 2016.

Strimvelis treats severe combined immunodeficiency (SCID) due to adenosine deaminase (ADA) deficiency. It is estimated that about a couple dozen children per year are diagnosed with ADA-SCID in the U.S. and Europe combined. One year on the market, the British pharma has confirmed that one patient has been treated with the drug. "A patient has been treated with Strimvelis and others have been referred and are currently being assessed for eligibility to receive the drug," GSK spokesperson Anna Padula told BioPharma Dive.

After the Glybera debacle, GSKs experience with Strimvelis will be telling, but there are also some up-and-coming gene therapies that may teach us more.

Gene therapy was originally regarded as one of those "no-brainer"approaches to curing genetically caused diseases. After all, if the DNA is broken, why not just fix it? Unfortunately, it turned out to be much more complicated.

Many of the challenges are around how new DNA is incorporated. One choice is to inject a viral vector attached to a payload that naturally integrates its genetic material into that of the patients. The other choice is to remove the patients cells, modify them, and return them, a process known as ex vivo therapy.

One of the early fears was that DNA would incorporate in the wrong place thereby not fixing the error, as well as creating a new one. That turned out to be a real worry with some of the first vectors, reinforced by early gene therapy treatments for SCIDS that led to T-cell leukemia in some treated boys. At least one of those boys died from the cancer they developed.

Further, there was the tragedy of Jesse Gelsingers death at the University of Pennsylvanias Institute of Human Gene Therapy in 1999. Eighteen-year-old Gelsinger was taking part in a trial aimed at treating ornithine transcarbamylase deficiency, but just days after receiving the therapy he died of massive organ failure, likely sparked by an immune reaction to the adeno-viral vector used.

Then there were treatments that just didnt work. Avigens gene therapy worked well in animals, producing adequate Factor IX levels for several years in models of hemophilia. But in clinical trials, only one patient responded, and that response lasted only four weeks. The patient, as one observer noted, had "touched the rainbow" only to watch it fade from view.

Beyond efficacy, manufacturing is still a challenge. "But we are getting better at that and in the selection of indications," said Scott Burger, principal at Advanced Cell and Gene Therapy. Because gene therapy is such a young field, Burger noted that "long-term monitoring of patients will be key." The boys who developed leukemia in the early SCID trial were all diagnosed a couple of years after treatment.

Every field has its ups and downs, but these tragic events left gene therapy with tremendous baggage. Still, some dogged proponents have soldiered on, and the news now more than a decade later seems to be getting a lot better.

"A new generation of vectors have dramatically improved the prospects for this field," said Geoff MacKay, President and CEO of AvroBio. "There are now hundreds of gene therapies that are in trials and many of them are a one time cure."

News about promising gene therapies in the clinic is sprouting up all the time.

BioMarin has a gene therapy for hemophilia A in Phase 2b. "We are far ahead in the development process and could potentially market the first gene therapy for this condition," said company spokesperson Debra Charlesworth. "The physician and patient community will be looking for strong clinical data," she added. "In addition we have commissioned a gene therapy manufacturing facility that will come online in the middle of this year."

GSK has a license to develop multiple new gene therapies with Fondazione Telethon and Ospedale San Raffaele, the same groups that helped produce Strimvelis. The agreement covers six additional treatments, including one for metachromatic leukodystrophy and one for Wiskott-Aldrich Syndrome. Padula reports that both of these are in clinical trials.

The next wave of gene therapies will focus on rare diseases like hemophilia and even inherited forms of blindness.Spark Therapeutics, for example,recently submitted a Biologics License Application (BLA) with the FDA for voretigene neparvovec, a gene therapy for the treatment of vision loss due to biallelic RPE65 mutation-associated retinal disease.

And Pfizer has inked deals with both Spark and Sangamo for gene therapies to treat different forms of hemophilia. Meanwhile, Biogen spin-off Bioverativhas picked up two gene therapies from Sangamo.

Scientific challenges remain considerable, though, and pricing will clearly be one of the biggest hurdles for gene therapies going forward. "Todays challenges are all around building a viable business model," said MacKay. That has not dampened enthusiasm for the blossoming field that has been rising and falling out of favor for at least two decades.

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A new wave of gene therapies ready to hit US shores - BioPharma Dive